Garo P. Basmadjian

Efficient synthesis of (±)-N-BOC-exo-2-(methoxycarbonyl)-7-Azabicyclo[2.2.1]heptane, a versatile intermediate for the synthesis of epibatidine and epiboxidine

N-BOC-exo-2-(methoxycarbonyl)-7-azabicyclo[2.2.1]heptane, an important intermediate for the synthesis of epibatidine and its analogs was efficiently synthesized from N-BOC-exo-2-(methoxycarbonyl)-7-azabicyclo[2.2.1]hepta-2,5-diene (5) via hydrogenation followed by reductive dehalogenation or via hydrodehalogenation followed by epimerization. The diene 5 was obtained by Diels-Alder reaction.

Tissue distribution of 3H-terbutaline in rabbits

Terbutaline is a widely used, selective beta 2-adrenergic agonist whose penetration into brain has not been demonstrated in laboratory animals. Although its tissue uptake has been reported in some animals, no uptake into brain has been demonstrated. A single dose of 20 microCi of 3H-terbutaline along with 10 mg/kg of unlabeled terbutaline was injected into a rabbit marginal ear vein. The distribution of 3H-terbutaline in several tissues was determined 0.5, 1, 3, or 6 hr later. Radioactivity in the brain was well-maintained over the 6 hr observation period. In most tissues, radioactivity peaked in less than 1 hr, then declined. Radioactivity in the urine was high at all time periods and was highest at 3 hr. Thus, terbutaline or a metabolite(s) does cross the blood-brain barrier in rabbits, and the radioactivity in the rabbit brain does not decrease during the 6 hours following terbutaline injection.

Dual-isotope measurement of lung water.

Iodine-131-labeled iodo-antipyrine and 99mTc-labeled erythrocytes were used to measure water content in lungs. These radioactive tracers were injected into 11 dogs with injured lungs. Blood samples were drawn and the animals sacrificed. The lungs were removed, weighed and homogenized. Samples of blood and lung homogenate were assayed for 131I and 99mTc. Samples were also weighed before and after drying to a constant weight at 70-76 degrees C. Extravascular lung water was determined by the dual-isotope technique and again by gravimetric analysis. The average ratio of the results from the two different methods was 1.14 +/- 0.20. The two methods were also compared by regression analysis and the correlation coefficient was 0.97 +/- 0.09.

Inherited, selective hyporesponsiveness to the analgesic action of nicotine in mice

THE acute dose-dependent analgesic activity of nicotine, as measured by the tail-flick assay, differed significantly between CD-1 and CF-1 outbred strains of mice. Differing responsiveness to the tail-flick stimulus did not explain this pharmacological effect. The inherent analgesic hyporesponsiveness of CF-1 mice was pharmacologically selective. Xilocaine and morphine produced an analgesic response of large magnitude in CF-1 mice. Reduced efficacy of nicotine in the CF-1 analgesia assay was not observed in its action on locomotor activity or in the induction of seizures and lethality. These findings have practical significance in identifying the importance of genotype in choice of strain for preclinical pharmacological studies of nicotine-induced analgesia and indicate that genetic analysis may provide a valuable tool for investigating the mechanism underlying the analgesic action of nicotine.

New 75Se-labeled radiopharmaceuticals: 2. Selenium derivatives of aralkylamines.

Two 75Se-labeled aralkylamines, 2-(3,4-methylenedioxyphenylseleno)ethylamine hydrochloride (75Se-6) and 1-methylseleno-1-phenylethylmethylamine hydrochloride (75Se-9), were prepared with high specific activity applying two different chemical means starting from [75Se]selenious acid. Tissue distribution studies in rats show high uptake in the lungs with lung/blood ratios of 27/1 and 2.3/1 at 10 min for compound 75Se-9 and 75Se-6, respectively. High adrenal uptake and adrenal-to-blood ratio (15/1 at 2 h) of compound 75Se-9 were observed. This study indicates that aralkylamines can accommodate a Se group and still show high uptake by the organs that contain appreciable amount of dopaminergic receptors.

2'-Substituted analogs of cocaine: synthesis and dopamine transporter binding potencies

A series of 2′‐substituted cocaine analogs (4‐8) was prepared and evaluated in an in vitro dopamine transporter (DAT) binding assay. Compounds 4‐7 were prepared by esterifying the 3β‐hydroxyl group of ecgonine methyl ester (3) using the appropriate acid chloride in the presence of Et3N and benzene. Compound 3 was obtained from cocaine (1) by hydrolysis using 1N HCl to afford ecgonine . HCl which was subjected to acid catalyzed esterification using methanol saturated with HCl gas. Compound 8 was obtained by hydrogenation of 7 using H2/Pd‐C. The IC50 values were calculated from displacement experiment of the radioligand [3H]WIN‐35,428 (2). 2′‐Aminococaine (8) showed high binding affinity to the DAT (14‐ and 1.3‐fold more active than cocaine and the radioligand 2, respectively). These results, along with previous results, emphasize the importance of a hydrogen‐bond donor group at the 2′‐position of cocaine to enhance binding affinity to the DAT.

Selective behavioral alterations on addition of a 4'-phenyl group to cocaine

We synthesized a cocaine analog in which a phenyl group was added at the para-position of the benzene ring of cocaine. This substitution caused a modest reduction (four-fold compared with cocaine) in binding potency for the primate (Papio) dopamine transporter as judged by displacement of [3H]WIN 35,428 binding from caudate/putamen membranes. Behavioral effects of this structural modification in the mouse were complex and selective, comprising absence of stimulation of locomotor activity, enhanced inhibition of locomotion and reduced lethal potency. Convulsant potency was unaltered. Substituents at the 4‘-position of cocaine are important in its actions. Simple changes in the chemical structure of this drug may produce complex and selective changes in its neurochemical and behavioral actions.

Dosimetry of iodoantipyrine

Dosimetry of iodoantipyrine labeled with radioactive iodine was determined by measuring the biodistribution of 131I-iodoantipyrine in 41 female rabbits. Following administration of the radiopharmaceutical, subjects were killed at 0.5, 6, 12, 17, 24, 36, and 48 h. Organs and samples of tissues and body fluids were assayed. Results were corrected for physical decay. Exponential functions were employed to describe the time-concentration curves; representative value would be the biological half life of 9.96±0.55 h for blood. Cumulated activity estimates for 123I, 125I and 131I were then computed. Extrapolation to absorbed dose in humans followed the formulation of the Medical International Radiation Dose (MIRD) Committee of the Society of Nuclear Medicine. The whole body absorbed doses are 7 μGray, 5 μGray and 29 μGray per MBq of 123I, 125I, and 131I administered respectively.